Association between fibrinogen‐to‐albumin ratio and functional prognosis of 3 months in patients with acute ischemic stroke after intravenous thrombolysis

Abstract Background The presence of high fibrinogen and low albumin levels in serum is associated with a negative prognosis in acute ischemic stroke (AIS). Fibrinogen‐to‐albumin ratio (FAR), a new inflammatory biomarker, may provide better prognostic insights in patients with AIS than separate evaluation of fibrinogen or albumin. The objective of this investigation is to examine the correlation between FAR and 3‐month functional prognosis after intravenous thrombolysis (IVT) in AIS patients. Methods The retrospective study recruited AIS patients who received IVT from June 2014 to December 2021. The 3‐month functional prognosis was assessed using the Modified Rankin Scale (mRS). A mRS score of ≤2 indicated a good outcome, whereas a mRS score of >2 suggested a poor outcome. Results A total of 591 AIS patients who underwent IVT were included and 147 patients (24.9 %) had a poor outcome. Among the 102 pairs of patients after propensity score matching, there was a significant association between FAR and 3‐month prognosis (adjusted OR, 1.19; 95% CI, 1.03–1.38; p = .020). The optimal FAR cutoff value was found to be 7.57, and even after stratifying patients based on this value, we still observed a significant correlation between high FAR level and poor outcome (adjusted OR, 2.08; 95% CI, 1.28–3.40; p = .003). Conclusions FAR may serve as a prospective biomarker of predicting 3‐month prognosis in AIS patients after IVT.

variables, including advanced age, male gender, National Institutes of Health Stroke Scale (NIHSS) score at admission (Romano et al., 2015) and elevated blood glucose levels (Miller et al., 2011).Apart from the NIHSS score, serum biomarkers may have a greater impact on the outcomes of AIS as potential risk factors.However, previous studies have paid little attention to the role of serum biomarkers in the prognosis.
Fibrinogen (FIB) has a significant correlation with platelet activation, fibrin formation, and increased plasma viscosity (Chapin & Hajjar, 2015).Elevated levels of FIB result in increased blood flow resistance, which promotes the formation of arterial plaque and thrombus (Tousoulis et al., 2011).Additionally, FIB participates in systemic inflammatory responses, inducing cytokine and chemotactic factor secretion, and promoting the release of active oxygen species, ultimately leading to brain injury (Luyendyk et al., 2019;Petersen et al., 2018).Albumin (ALB), as a negative inflammatory biomarker, has multiple functions including antiapoptotic, antioxidant, and anti-inflammatory activities (Oettl & Stauber, 2007).It plays a crucial role within body, including inhibiting platelet activation and aggregation, reducing neurotoxicity in patients with stroke, and scavenging free radicals to improve functional prognosis (Gabay & Kushner, 1999;Zhang et al., 2016).
Besides, ALB accumulates in areas of inflammation; therefore, it can serve as an ideal drug delivery platform (Sleep, 2015).Fibrinogento-albumin ratio (FAR), a new inflammatory biomarker, may provide better prognostic insights in patients with AIS than separate evaluation of fibrinogen or albumin.In certain thrombotic diseases, such as ST-segment elevation myocardial infarction (Karahan et al., 2016), lacunar stroke (Zheng et al., 2021), and pontine stroke (Zhai et al., 2022), elevated FAR levels have been identified as a reliable indicator of disease severity.Moreover, elevated FAR levels have been linked to complications in cerebral infarction, including hemorrhagic transformation and poststroke pneumonia (Lin et al., 2021;Yang et al., 2023).However, it is currently unclear whether elevated FAR levels are associated with 3-month prognosis in AIS patients after IVT.Therefore, the primary objective of the study is to elucidate the correlation between FAR and the 3-month prognosis in patients with AIS following IVT.

Study population
This study was conducted retrospectively and observed.Patients with AIS who received IVT therapy using rt-PA within 4.5 h of symptom onset and were subsequently admitted to Shanghai East Hospital between June 2014 and December 2021 were enrolled in the study.
All patients were managed in the stroke unit and received standard care.This study was approved by the Ethics Committee of Shanghai East Hospital Affiliated to Tongji University.The final analysis included participants who met the specified criteria.
Inclusion criteria: 1. Diagnosis of AIS and received IVT therapy within 4.5 h after onset; 2. Age ≥18 years old.
Exclusion criteria: 1. Clinical data is not complete; 2. Diagnosed with stroke mimics;

Received endovascular treatment after IVT;
4. There are other serious internal medicine system diseases that coexist before stroke.

Clinical information
The following retrospective data for each patient prior to IVT therapy was collected.and severe (>20) groups.

Laboratory data
Laboratory parameters included high-sensitivity C-reactive protein (Hs-CRP), fasting blood glucose (FBG), glycosylated hemoglobin (Hba1c), fibrinogen (FIB), and albumin (ALB).Measurements were conducted before IVT therapy, except for Hba1c levels, which were assessed upon admission to the inpatient department.The FIB and ALB were measured using the Roche cobas 8000 C702 chemiluminescence immunoassay technology produced by Roche Diagnostics.The FAR can be determined using the formula: FAR = FIB/ALB.In this study, we focus on the FAR metric.However, due to its typically small values, for better understanding and interpretation purposes, we have applied a scale transformation by multiplying the values by 10 2 .This transformation does not affect the substantive content or conclusions of our model; it simply enhances its comprehensibility.

Clinical outcomes
A trained and qualified neurologist, who was blind to the particulars of the situation, ascertained all subsequent clinical outcomes among the enrolled patients based on a 3-month poststroke onset, via telephone consultations or outpatient follow-up visits.Clinical outcomes were evaluated using the mRS.A mRS score of ≤2 indicated a good outcome, whereas a mRS score of >2 suggested a poor outcome (Broderick et al., 2017).

Statistical analysis
The replacement, with a caliper set at 0.05, in order to minimize any potential differences between matched pairs.The FAR between the two patient groups was conducted using binary logistic regression, while an optimal FAR cutoff for predicting clinical outcomes was determined through the utilization of a receiver operating characteristic (ROC) curve.

RESULTS
A total of 709 AIS patients received IVT therapy from June 2014 to December 2021 were screened; 101 patients were excluded because of the exclusion criteria and 17 patients were excluded owing to an absence of follow-up data.Finally, 591 subjects were included for analysis.Through the utilization of the PSM method, a total of 102 pairs of patients were successfully matched between the two groups.The process of selecting patients is illustrated in Figure 1.
Ultimately, 75.1% of patients (n = 444) achieved a good outcome, while 24.9% (n = 147) experienced a poor outcome.Based on the baseline characteristics of the participants, early baseline data categorized by good and poor outcomes were displayed in Table 1.The observed disparities between the two groups were as follows: age   3).
The analysis of the ROC curve demonstrated that the FAR exhibited an area under the curve (AUC) value of 0.638 (95 % CI, 0.58 -0.69; p < .001)when predicting 3-month prognosis in AIS patients after IVT (Figure 3).The FAR level of 7.57 was considered the optimal cutoff value for predicting clinical outcomes.The FAR demonstrated a predictive performance with a sensitivity of 48.98% and specificity of 77.48% (Table S1).
To further elucidate the association between FAR levels and functional prognosis in AIS patients following IVT, all patients were stratified into two groups based on the optimal cutoff value of FAR: a low FAR group (≤7.57) and a high FAR group (>7.57) (Table 4).The distribution of mRS between these two groups is shown in Figure 4 5).

DISCUSSION
Many factors are associated with the prognosis of patients who receive IVT after AIS.However, previous studies have paid little attention to the role of serum biomarkers in the prognosis.This study primarily investigates the correlation between FAR and the 3-month prognosis.
The correlation between FAR and 3-month prognosis of AIS patients after IVT is determined by the levels of FIB and ALB.The plasma glycoprotein FIB is synthesized by the liver and represents the most abundant coagulation factor in the human body (Levy & Goodnough, 2015).FIB is pivotal in the cascade of clot formation (Chapin & Hajjar, 2015) and is intimately linked with platelet activation, fibrin formation, and increased plasma viscosity.
Elevated levels of FIB lead to increased resistance in blood flow, reduced velocity, and the maintenance of a hypercoagulable state, ultimately promoting the formation of arterial plaques and thrombi (Tousoulis et al., 2011).In addition, FIB is involved in systemic inflammatory responses (Luyendyk et al., 2019).FIB acts as a ligand for diverse cell surface receptors, mediating cell-to-cell adhesion between leukocytes and endothelial cells (Yakovlev & Medved, 2018).FIB binds to receptors on astrocytes in the brain, which triggers the secretion of cytokines and chemokines, facilitating the release of reactive oxygen species, ultimately resulting in cerebral injury (Petersen et al., 2018).Elevated levels of serum matrix permeability, and ultimately causing brain tissue damage (Iadecola et al., 2020).Furthermore, FIB can directly increase the permeability of the blood-brain barrier (BBB) by acting on cerebral endothelial cells, disrupting the integrity of the BBB, and subsequently causing neuroinflammation and neuronal damage (Petersen et al., 2018) neurological impairment and enhance their overall quality of life (Chen et al., 2018).
ALB, as a negative inflammatory biomarker, exhibits various functions such as antiapoptotic, antioxidant, and anti-inflammatory effects (Oettl & Stauber, 2007).It plays a vital physiological function within the body, specifically by inhibiting platelet activation and aggregation (Gabay & Kushner, 1999).High levels of albumin can decrease neurotoxicity and scavenge free radicals, thereby improving functional outcomes in patients with AIS (Zhang et al., 2016).Conversely, hypoal-buminemia is related to adverse functional outcomes in ischemic stroke (Dziedzic et al., 2004).ALB can effectively reduce infarct volume and cerebral edema while decreasing BBB permeability in ischemic stroke (Park et al., 2017).Studies have been conducted on the use of intravenous ALB infusion to improve outcomes in patients with AIS (Huang & Xiao, 2021).However, the specific clinical results remain unclear.Moreover, ALB accumulates at the site of inflammation; therefore, it can serve as an ideal platform for drug delivery (Sleep, 2015).
TA B L E 2 Baseline characteristics and laboratory results in patients with good and poor outcomes at 3 months after PSM.The FAR is an emerging systemic inflammatory biomarker derived from the levels of fibrinogen and albumin.It has the potential to be more effective than measuring FIB or ALB individually in predicting prognosis following IVT.ALB interacts with FIB, leading to impaired activity of FIB (Galanakis, 1992).Elevated levels of FAR indicate higher levels of FIB or lower levels of ALB.Elevated levels of FAR have been identified as markers of disease severity in certain thrombotic conditions, such as ST-segment elevation myocardial infarction, lacunar stroke, and pontine stroke (Karahan et al., 2016;Zhai et al., 2022;Zheng et al., 2021)

F I G U R E 4
The distribution of mRS between the high FAR group and low FAR group.The mRS scores in the high FAR group were significantly higher than those in the low FAR group (p < .001).
This study investigates the association between FAR and functional prognosis of 3 months after IVT in patients with AIS.First, our study findings indicate that patients with poor outcome had significantly higher baseline levels of FAR compared to those with good outcome.
After adjusting for potential confounding variables, we observed an independent correlation between FAR and 3-month prognosis.Second, the analysis of the ROC curve indicated that a FAR level of 7.57 was identified as the optimal cutoff value for predicting poor outcome occurrence.In addition, when stratifying AIS patients based on FAR's optimal cutoff value, we found that the high FAR group had a larger portion of poor outcome than the low FAR group.After adjusting for potential confounding factors, we observed an independent connection between higher levels of FAR and the occurrence of poor outcome.Consequently, our study has revealed an independent correlation between FAR and 3-month prognosis in AIS patients after IVT.Patients with elevated FAR levels exhibit more severe neurologic deficits and have poorer outcome.
Our research may be subject to certain limitations.First, our study was based on a retrospective database from a single center, which had limited sample size and regional restrictions, potentially introducing unavoidable subjective selection bias.Further validation through multicenter and large-sample studies is warranted.Second, our FAR data were obtained from pre-IVT measurements, without further followup to observe the changes in the ratio after IVT.Third, no nutritional assessment was conducted upon admission, and the nutritional status could potentially influence the changes in the FAR, which may be associated with the prognosis of cerebral infarction.

F
The flow chart of the selection of acute ischemic stroke patients who underwent intravenous thrombolysis.The violin plot in distribution of FAR between good outcome and poor outcome groups.***p < .001.metalloproteinase-9 (MMP-9) during the acute phase of ischemic stroke are indicative of an augmented risk for mortality and significant disability(Maestrini et al., 2020;Zhong et al., 2017).FIB can activate endothelial cells, resulting in the production of MMP-9(Sulimai et al., 2023).MMP-9 degrades endothelial junction proteins, compromising endothelial cell integrity, increasing cerebral vascular analysis of FAR for predicting 3-month functional prognosis in AIS patients after IVT.The AUC of FAR for predicting 3-month functional prognosis is 0.638.

Table 2
).The univariate logistic regression analysis unveiled a statistically significant association between FAR and clinical outcomes (OR, 1.15; 95% CI, 1.02-1.30;p = .024).Following adjustment for age, gender, stroke severity, TOAST, smoking, AF as well as Hs-CRP and FBG levels in a multivariable logistic regression model, our findings indicate that FAR remains significantly linked to clinical outcomes despite accounting for these potential confounders (adjusted OR, 1.19; 95% CI, 1.03-1.38;p = .020)(Table Baseline characteristics and laboratory results in patients with good and poor outcomes at 3 months.Hs-CRP, high-sensitivity C-reactive protein; IQR, interquartile range; NIHSS, National Institutes of Health Stroke Scale; OTT, the time from onset to treatment; TIA, transient ischemic attack; TOAST, the Trial of Org 10172 in Acute Stroke Treatment.
. The utilization of FIB depletion agents in patients with AIS can help mitigate TA B L E 1 Hs-CRP, high-sensitivity C-reactive protein; IQR, interquartile range; NIHSS, National Institutes of Health Stroke Scale; OTT, the time from onset to treatment; PSM, propensity score matching; TIA, transient ischemic attack; TOAST, the Trial of Org 10172 in Acute Stroke Treatment.
Binary logistic regression for the clinical outcomes at 3 months after PSM.Age, gender, stroke severity, TOAST, smoking, AF, Hs-CRP, FBG, and FAR were included. a Baseline characteristics and laboratory results of patients in the low (≤7.57) and high (>7.57)FAR groups.Multivariate analysis of patients in the low (≤7.57) and high (>7.57)FAR groups.< .05.Abbreviations: AF, atrial fibrillation; CI, confidential interval; FBG, fasting blood glucose; Hs-CRP, high-sensitivity C-reactive protein; NIHSS, National Institutes of Health Stroke Scale; OR, odds ratio; TOAST, the Trial of Org 10172 in Acute Stroke Treatment.
month prognosis in AIS patients after IVT.Elevated FAR levels enhance the probability of poor outcome in AIS patients after IVT.The confirmation of these findings regarding the prognosis of patients with AIS after IVT necessitates further multicenter longitudinal studies.TA B L E 4